Osteoarthritis and Cartilage 18 (2010) 876e882

Review

The infrapatellar fat pad should be considered as an active osteoarthritic joint

tissue: a narrative review
S. Clockaerts yz *, Y.M. Bastiaansen-Jenniskens z, J. Runhaar z, G.J.V.M. Van Osch z, J.F. Van Offel y,
J.A.N. Verhaar z, L.S. De Clerck y, J. Somville y
y University of Antwerp, Department of Medicine, Belgium
z Erasmus MC, University Medical Center Rotterdam, The Netherlands

a r t i c l e i n f o s u m m a r y

Article history: Introduction: Osteoarthritis (OA) of the knee joint is caused by genetic and hormonal factors and by
Received 8 December 2009 inflammation, in combination with biomechanical alterations. It is characterized by loss of articular
Accepted 22 March 2010 cartilage, synovial inflammation and subchondral bone sclerosis. Considerable evidence indicates that
the menisci, ligaments, periarticular muscles and the joint capsule are also involved in the OA process.
Keywords: This paper will outline the theoretical framework for investigating the infrapatellar fat pad (IPFP) as an
Infrapatellar fat pad
additional joint tissue involved in the development and progression of knee-OA.
Knee osteoarthritis
Methods: A literature search was performed in Pubmed from 1948 until October 2009 with keywords
Adipose tissue
Inflammation
InFrapatellar fat pad, Hoffa fat pad, intraarticular adipose tissue, knee, cartilage, bone, cytokine, adipo-
kine, inflammation, growth factor, arthritis, and OA.
Results: The IPFP is situated intracapsularly and extrasynovially in the knee joint. Besides adipocytes, the
IPFP from patients with knee-OA contains macrophages, lymphocytes and granulocytes, which are able
to contribute to the disease process of knee-OA. Furthermore, the IPFP contains nociceptive nerve fibers
that could in part be responsible for anterior pain in knee-OA. These nerve fibers secrete substance P,
which is able to induce inflammatory responses and cause vasodilation, which may lead to IPFP edema
and extravasation of the immune cells.
The IPFP secretes cytokines, interleukins, growth factors and adipokines that influence cartilage by
upregulating the production of matrix metalloproteinases (MMPs), stimulating the expression of pro-
inflammatory cytokines and inhibiting the production of cartilage matrix proteins. They may also
stimulate the production of pro-inflammatory mediators, growth factors and MMPs in synovium.
Conclusion: These data are consistent with the hypothesis that the IPFP is an osteoarthritic joint tissue
capable of modulating inflammatory and destructive responses in knee-OA.
Ó 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Introduction Considering the intraarticular location of the IPFP, the metabolic

In the recent past, knee osteoarthritis (OA) was considered as
a pathologic condition that affects cartilage and bone. We now
appreciate that all joint tissues, including the synovium, menisci,
ligaments, periarticular muscles and the joint capsule are involved1.
In addition to these structures, the knee joint also contains adipose
tissue: the infrapatellar fat pad (IPFP)2. Although it has been known
that adipose tissue secretes inflammatory mediators that are able
to influence cartilage and synovium, a theoretical framework for
a role of the IPFP in knee-OA has not been described3.
properties of adipose tissue and the fact that the OA disease process
involves all the joint tissues, it is likely that the IPFP could also be
involved in knee-OA. Our hypothesis is that immune cells could
infiltrate IPFP as a result of knee-OA and that the combination of
immune cells, nerve fibers and adipocytes could then contribute to
the disease process by producing and releasing inflammatory
mediators, capable of modifying inflammatory and destructive
responses in cartilage and synovium (Fig. 1). In this article, an
overview is given of literature that supports this hypothesis.
Methods

* Address correspondence and reprint requests to: Stefan Clockaerts, University

Hospital of Antwerp, Department of Orthopaedic Surgery and Traumatology,
A literature search was performed in Pubmed from 1948 until
Wilrijkstraat 10, 2650 Edegem, Belgium. Tel: 0032-486-62-76-84. October 2009 using keywords intrapatellar fat pad, Hoffa fat pad,
E-mail address: stefan.clockaerts@ua.ac.be (S. Clockaerts). inFrapatellar adipose tissue, knee, cartilage, bone, cytokine,

1063-4584/$ e see front matter Ó 2010 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.joca.2010.03.014
 S. Clockaerts et al. / Osteoarthritis and Cartilage 18 (2010) 876e882 877

Synovial layer

Articular cartilage
Infrapatellar
fat pad

INFLAMMATION Synovial
fluid
Fat pad edema
Extravasation of WBC Interleukins
Growth factors
Nitric oxide
lymphocytes Leukotrienes
granulocytes Prostaglandines
monocytes

Blood Substance P Leptin

vessel Adiponectin
NAMPT
Resistin

Adipocytes
Osteophytosis
Sensory nerve
(C-fibre)
Articular cartilage

Fig. 1. A schematic overview of the IPFP as an active osteoarthritic joint tissue. The IPFP shows signs of inflammation secondary to OA of the knee joint. The IPFP contains adipocytes
and has an increased number of immune cells such as lymphocytes, monocytes and granulocytes that have migrated from the blood circulation. Substance P nerve fibers are also
present in the IPFP and contribute to the immune regulation within the IPFP by the secretion of substance P. Substance P is able to induce extravasation of white blood cells and is
also known to enhance inflammation in white blood cells. The combination of these cells is able to secrete adipokines such as leptin, adiponectin, NAMPT and resistin, but also ILs,
growth factors, nitric oxide, leukotrienes and prostaglandins which have shown to influence cartilage, synovium and osteophyte formation.

adipokine, inflammation, growth factor, arthritis, OA. We excluded
papers that were not written in English. Cadaver knee joints were
dissected to make photographs and figures.
Results
Inflammation in OA
Considerable evidence indicates that OA has a multifactorial
etiology with a combination of biomechanical, genetic, inflamma-
tory and hormonal factors4e7. Abnormal biomechanical loading is
an etiological factor in OA that can be caused by partial or total
meniscectomy, malalignement, joint instability, muscle weakness
or peripheral neuropathy, and obesity5,8. In addition to tissue
damage or wear, repeated overloading of joints activates mecha-
noreceptors in chondrocytes and osteoblasts, which in turn acti-
vates inflammatory pathways that lead to the production of
cartilage degradation mediators9e12.
Several lines of evidence indicate that genetic abnormalities can
result in an early initiation of OA. For knee-OA, the influence of
genetics on the onset of OA is believed to be between 39 and 65%.
Many of these genes affect extracellular cartilage matrix and
cartilage signaling molecules7.
Inflammatory pathways are known to play a role in the devel-
opment of OA. Clinical features of inflammation, such as joint pain,
swelling and stiffness, are indeed present during clinical exami-
nation13. Inflammatory mediators, such as interleukin (IL)1b and
tumor necrosis factor (TNF)a, are released by cartilage, bone,
synovium and other surrounding joint tissues and are capable of
inducing matrix metalloproteinases (MMPs), aggrecanases and
other catabolic genes5,14. This causes remodeling of the extracel-
lular cartilage matrix. These inflammatory mediators induce the
production of prostaglandin E2 by stimulating the expression or
activity of cyclooxygenase (COX)2, microsomal prostaglandin E2
synthase 1 (mPGES1), and soluble phospholipase A2 (sPLA2)14.
They also upregulate the production of nitric oxide via inducible
nitric oxide synthetase (iNOS) and induce pro-inflammatory cyto-
kines such as IL1, TNFa, IL6, leukemia inhibitory factor (LIF), IL17,
IL18, and chemokines, including IL8. The expression of a number of
genes associated with a differentiated chondrocyte phenotype,
including collagen type II is suppressed by inflammatory mecha-
nisms5,14,15. Transforming growth factor (TGF)b produced by
synovial macrophages, is shown able to induce the formation of
osteophytes in animal studies16,17. Inflammatory events in the
subchondral bone layer may induce hypertropic differentiation of
chondrocytes or stimulate chondrocytes in a paracrine man-
ner18e20. However, it is not known whether the subchondral bone
inflammation is partly caused or stimulated by inflammatory
mediators present in osteoarthritic joints.
Obesity is associated with OA
Obesity and high body mass index are associated with a higher
incidence risk of OA9. Changed kinetics of weight-bearing joints can
878 S. Clockaerts et al. / Osteoarthritis and Cartilage 18 (2010) 876e882
lead to the initiation and progression of OA, and obesity could
enhance this mechanism by increasing the loading forces21,22.
However, non-weight-bearing joints such as joints of the hand also
have higher incidence risk for OA in obese people compared to
healthy people23e27. Furthermore, Toda et al. showed that the loss
of body fat is more beneficial for symptomatic relief in knee-OA
than the loss of body weight28. Wang reported a correlation
between the risk of primary knee or hip replacement for OA and
central obesity or adipose mass. The latter could be explained by
the higher amount of visceral adipose tissue, which is known to
secrete more pro-inflammatory cytokines compared to peripheral
subcutaneous adipose tissue29. These data suggest that adipose
tissue is an endocrine organ that is able to exert metabolic effects
on the joint tissues.
The IPFP or Hoffa’s fat pad is located in the knee joint
The IPFP or Hoffa fat pad was first described by Albert Hoffa in
190430. It is situated in the knee underneath the patella, between
the patellar tendon, femoral condyle and tibial plateau, where it
completely fills the potential spaces between these structures
(Fig. 2). Therefore, it is located closely to the synovial layers and
cartilage surfaces of the knee joint (Figs. 2 and 3). The IPFP is
composed of a fibrous scaffold, on which constitutional fat tissue is
embedded, which is developed under the influence of sex
hormones. The joint facing surface is covered by the antero-inferior
synovial membrane, thus the IPFP localization can be described as
intracapsular and extrasynovial31,32. It attaches to the lower border
of the inner non-articulating surface of the patella, to the notch
between the two condyles of the femur by running continuously
with the infrapatellar plica posterosuperiorly, and to the perios-
teum of the tibia and the anterior part of the menisci2 (Fig. 3). An
extensive anastomotic network of vessels protects the IPFP against
Fig. 2. A midsagittal plane of the knee joint. This figure shows the location of the IPFP
(1) and also the presence of other smaller fat pads in the knee joint: posterior fat pad
(2), anterior suprapatellar fat pad (3) and posterior suprapatellar fat pad (4). The IPFP is
located inferior from the patella and posterior from the patella tendon. It is covered by
the joint capsule (white arrow) from anterior and the synovium (black arrow) on his
joint facing surface. Thus it is located intracapsular, but extrasynovial. Also notice its
close contact with articulating cartilage surfaces.
Fig. 3. A dissection of a left knee in flexion showing the IPFP from an anterior view
(broken lines). The patella tendon has been dissected proximally and retracted to show
the joint facing surface of the patella and the IPFP. The IPFP is located in the knee joint
and closely to the articulating cartilage surfaces and the synovium. Notice the
attachments of the IPFP at the lower border of the patella (black arrows). The
attachment at the intercondylar region with the ligamentum mucosum (white arrow)
is located before the anterior cruciate ligament.
necrosis during extensive surgical exposures or arthroscopic
procedures33. Only the central portion of the IPFP has a more
limited vascular network. It is supplied by branches of the superior
and inferior genicular artery. The inferior portion of the anasto-
motic ring passes through the IPFP and supplies part of the
patella31,34,35. Many studies mention that the IPFP is innervated by
the posterior articular branch of the tibial nerve36e38. However, in
one of the most detailed studies about innervation of the knee,
Gardner39 describes branches rising from the saphenous, tibial and
obturator nerves, and the nerve to the vastus medialis, innervating
the anteromedial portion of the IPFP. The anterolateral part of the
IPFP is innervated by articular branches from the nerve to the
vastus lateralis, the tibial nerve, recurrent peroneal nerve and
common peroneal nerve. These branches accompany blood vessels
throughout the IPFP39.
IPFP facilitates the distribution of synovial fluid and may act to
absorb forces through the knee joint. Other functions of the IPFP
have not yet been determined. Pathologic processes that occur
within the IPFP are Hoffa disease, chondromas, nodular synovitis
and surgery related complications. Other small fat pads of the knee
joint have been mentioned: a posterior knee fat pad, an anterior
suprapatellar fat pad (quadriceps) and a posterior suprapatellar fat
pad (prefemoral) (Fig. 2)40.
The IPFP contains cells capable of modifying the OA disease process
Once it was thought that white adipose tissue acted only as
a reservoir for excess calories that are stored as triacylglycerols. After
the discovery of leptin in 1994 it became tangible that the white
adipose tissue could play an active role in physiologic and pathologic
processes, including immunology and inflammation41,42. The
adipose tissue is considered as a specialized form of connective
tissue, which contains large numbers of adipocytes, fibroblasts,
macrophages, leukocytes, and other cells involved in inflammation.
These cells are present in an intercellular matrix consisting of
collagen and elastic fibers, on which network epithelial structures
can rest and muscle and nervous tissue are embedded41.
The IPFP is a very sensitive structure together with the syno-
vium43. This is due to the presence of peptidergic C-fibers, nerve
 S. Clockaerts et al. / Osteoarthritis and Cartilage 18 (2010) 876e882 879

fibers staining positive for substance P44. The human OA IPFP We conclude that IPFP contains inflammatory cells and
contains even more small sized nerves compared to medium- or substance P nerve cells that could be able to influence inflamma-
large sized substance P nerves45. This suggests that the IPFP tory and destructive responses in knee-OA. Substance P nerve cells
contains part of the terminal sensory innervation for the knee joint in the IPFP could also play a role in the pain pathophysiology of
and could be an important source of pain in knee-OA. knee-OA.
The highest rates of substance P nerves are found around vessels
of IPFP: substance P causes vasodilation that leads to extravasation
Adipose tissue as an endocrine organ
of immune cells and causes IPFP edema. In turn, edema leads to soft
tissue impingement, ischemia and lipomatous tissue necrosis44.
Adipose tissue secretes cytokines, ILs, growth factors and adi-
The presence of IPFP edema was investigated in vivo by Lawson
pokines in an endocrine, autocrine or paracrine manner. These
et al. on MRI in patients with Lyme arthritis. Results of this study
inflammatory mediators are found in synovial fluid and are able to
indicate that IPFP edema can develop as a result of arthritis46.
influence the cartilage and synovium metabolism3,61,62. The
Ischemia induces the release of neuro-tropin neural growth factor,
immune cells present in the adipose tissue could be responsible for
which in turn activates the release of substance P. This type of
most of the production and release of inflammatory mediators,
autostimulation may cause chronicity of inflammation of the IPFP
except for leptin and adiponectin, which are mainly secreted by
in joint diseases44. O’Shaughnessy et al. showed that substance P
adipocytes41 (Fig. 1).
induces the production of nitric oxide in rheumatoid synoviocytes
Interesting adipokines are leptin and adiponectin, as they are
and experimental models of inflammation47. Furthermore, it
secreted in high amounts by adipose tissue41,61,63. Leptin was
stimulates IL1b, TNFa, nuclear factor kB and superoxide anion
thought to be beneficial for OA, because injection of leptin in a knee
production in various cell types. Substance P has also a strong effect
joint upregulated proteoglycan synthesis, production of growth
on fibroblast activation and extracellular matrix production45.
factors and stimulated its own synthesis in different joint
Sympathetic nerve fibers are known to secrete anti-inflamma-
tissues3,61. However, recent research has contradicted this idea. At
tory norepinephrine and endogenous opiods that are able to inhibit
present, leptin is known to stimulate IL1b production, to increase
pain perception in a bidirectional cross talk with substance P
the effect of pro-inflammatory cytokines and induce the expression
fibers45. In healthy synovium the density of sensory vs sympathetic
of MMPs in the OA cartilage3,64e68. Leptin is able to activate nitric
nerve fibers is balanced at 1:148. In synovium from rheumatoid
oxide synthase synergistically with interferon-g or to enhance
arthritis patients, the preponderance of the substance P positive
activation of nitric oxide synthase 2 by IL165. Leptin also facilitates
nerve fibers over sympathetic nerve fibers is approximately 8:1. For
the activation of macrophages, neutrophils, dendritic cells, natural
the IPFP, the ratio of sensory vs sympathetic nerve fibers is higher in
killers cells and Th1 cells69.
patients with anterior knee pain after total knee arthroplasty then
Adiponectin has been cited as a protective adipokine against
in patients with knee-OA45. Whether the density of sensory nerve
obesity and vascular diseases, but might act as a pro-inflammatory
fibers was higher than normal in the IPFP of knee-OA patients has
agent in joint diseases70. Adiponectin induces MMP1 and IL6
not yet been established. Based on these findings, we conclude that
production in synovial fibroblasts, which are known to have adi-
substance P nerves are present in IPFP and can act as inflammatory
ponectin receptors71. The presence of adiponectin receptors in
cells, besides the well described sensory function of these nerves.
chondrosarcoma cells, capable of inducing type 2 nitric oxide
synthase, suggests that adiponectin receptors are also present in
An increased amount of immune cells, edema, fat necrosis and
normal or OA chondrocytes72. Indeed, adiponectin treated chon-
fibrosis was reported in subsynovial IPFP in animal models of
drocytes produce IL6, MMP3, MMP9 and monocyte chemo-
induced arthritis, together with signs of alterations in joint diseases
attractant protein (MCP)163.
that involve synovial proliferation on MRI images31,49e52. Inflam-
Other adipokines are resistin and nicotinamide phosphor-
matory cell infiltrations were present in 36% of Hoffa fat pad
ibosyltransferase (NAMPT). Resistin is elevated after traumatic joint
specimens collected from patients with knee-OA while severe
injuries and induces production of inflammatory cytokines and loss
fibrosis was present in 33% of cases53. An OA animal model revealed
of proteoglycans in cartilage. The injection of resistin into mice
that the wet weight of IPFP in monoiodoacetate injected joints was
joints induces arthritis-like conditions70,73. NAMPT seems to have
two-fold higher than the vehicle controls. Numbers of neutrophils,
a pro-inflammatory effect on chondrocytes and synovial fibro-
eosinophils and basophils, and in particular monocytes were
blasts70,74,75. The role of adipokines on bone is not yet clarified.
increased37. Jedrzejczyk et al. also found lymphocytes in the IPFP54.
Leptin and resistin may stimulate bone formation and adiponectin
The infiltration of immune cells in synovium could contribute to
might have an inhibitory effect76.
the OA disease process by the production of pro-inflammatory and/
Many other inflammatory mediators such as IL1a and b, TNFa,
or pro-fibrotic cytokines16,17,55,56. Based on the anatomical location
IL4, IL6, IL8, IL10, IL18, IL1 receptor antagonist, MCP1, prostaglandin
of the IPFP, it is possible that similar processes exist for immune cells
E2, nitric oxide and growth factors such as vascular endothelial
in the IPFP. Cartilage breakdown molecules may activate monocytes
growth factor (VEGF), TGFb and fibroblast growth factor (FGF)2 are
by binding to receptors that are associated with receptors of innate
produced by adipose tissue and have shown to be involved in joint
immunity57. Activated macrophages produce various growth
diseases3,41.
factors, cytokines and enzymes that enhance osteophyte formation,
mitigate cartilage breakdown by MMP activity, induce joint effusion
by vasodilation and might influence subchondral bone metabolism. IPFP produces and releases inflammatory mediators in the knee joint
Neutrophils play a role in cartilage breakdown and necrosis of
adipose tissue by the production of cytokines such as IL1, IL8 and The adipokines leptin, resistin and adiponectin are found in the
MMP837,58. Eosinophils and basophils release histamine that synovial fluid61,62,67,77. The concentration of adipokines in the
increases production of matrix degrading enzymes and pro- synovial fluid differs from serum levels. Resistin and adiponectin
inflammatory mediators in synovial fibroblasts and cartilage59. are present in lower amounts in the synovial fluid than in circu-
Lymphocytes from OA joints express Th1 cytokines which can lating blood, while leptin is present in higher amounts66,77. A
directly degrade cartilage or activate macrophages through cellecell correlation between leptin concentration in the synovial fluid and
interaction to produce cartilage degrading mediators60. severity of knee-OA has been shown by Ku et al.78.
880 S. Clockaerts et al. / Osteoarthritis and Cartilage 18 (2010) 876e882
The presence of adipokines in the knee joint cannot be
explained by a higher permeability of the inflamed synovium alone,
because resistin is present in lower concentration in synovial fluid
than leptin, although its molecular weight is similar79,80. Leptin is
present in higher amount in synovial fluid from female OA patients,
but interestingly not in male OA patients. Except for adiponectin,
the synovial fluid levels of resistin and leptin appears to be higher
for women then for men. This effect cannot be explained by the
higher serum levels of leptin in woman, caused by influence of sex
hormones, because the synovium fluid/serum level ratios between
men and women are also different66.
Ushiyama et al. showed that the human OA IPFP contained
significant protein levels of FGF2, VEGF, TNFa and IL6. These cyto-
kines were also measured in the synovial fluid. Although synovial
fluid levels and IPFP content did not correlate, a similar distribution
of FGF2 and VEGF content was found in human OA synovium
compared to IPFP81. Presle showed that cultured explants of IPFP
produced large amounts of adiponectin and leptin, although
surprisingly explants obtained from osteophytes produced even
more leptin66.
The amount of IL6, soluble IL6 receptor and adiponectin that is
produced by the IPFP is higher than in subcutaneous adipose tissue
from obese people, although the production of leptin is lower.
These data, together with a decrease of genes related to lipid
metabolism in the IPFP, indicate that the IPFP should be regarded as
adipose tissue with its own characteristics82.
Intraarticular production of inflammatory mediators can occur
in different joint tissues such as cartilage, synovium, menisci or
osteophytes66. Based on these findings, we conclude that IPFP is
also able to produce and excrete important inflammatory media-
tors directly into the knee joint.
Discussion
This article reviews some significant points that could explain
the role of the IPFP in the disease process of knee-OA.
Inflammation plays an important role in the etiopathogenesis of
OA. The association between obesity and OA cannot only be
explained by biomechanical alterations, but also by the inflam-
matory properties of adipose tissue. The IPFP can be regarded as
a special form of adipose tissue due to its location, which is in close
contact with synovial layers and articulating cartilage.
Infiltration of immune cells has been demonstrated in the IPFP
in human OA joints and in animal models for arthritis and OA.
Furthermore, nociceptive nerve fibers are present that can cause
anterior pain and are capable of maintaining inflammation by the
release of substance P. The combination of adipocytes, immune and
nerve cells IPFP produces and secretes adipokines, but also cyto-
kines, chemokines and growth factors that are capable of altering
cartilage and synovium.
Further in vitro and in vivo studies should be performed to
confirm the release of inflammatory mediators in the synovial
compartment. It should be investigated whether the IPFP from
knee-OA patients produces more inflammatory mediators than
healthy IPFP and whether IPFP from obese people differs from
non-obese people in content or production of cytokines.
Furthermore, adipose tissue secretes anti-inflammatory media-
tors such as FGF2, IL4 or IL10, which could have beneficial effects
on cartilage and synovium41. Therefore, effects of the combina-
tion of all factors secreted by the IPFP on cartilage should be
explored. It should be investigated whether substance P fibers
are present in higher amounts in the IPFP from osteoarthritic
knees as compared to healthy knee joints. Furthermore, their
potential role in pain and inflammation in knee-OA should be
elucidated.
We conclude that IPFP could play an important role in the
initiation and progression of knee-OA and should be further
investigated in search for new therapeutic strategies.
Conflict of interest
All authors disclose any financial and personal relationships with
other people or organizations that could inappropriately influence
this work.
Acknowledgments
The authors would like to thank D. Malan and F. Van Glabbeek
for providing anatomical figures and photographs. The research of
Yvonne Bastiaansen-Jenniskens is funded by the Dutch Arthritis
Association and Top Institute Pharma.
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